Abuse-resistant mucoadhesive devices for delivery of buprenorphine

ABSTRACT

The present invention provides abuse deterrent mucoadhesive devices for delivery of buprenorphine. Each device comprises a mucoadhesive layer and a backing layer, and the pH in each layer is selected, such that absorption of buprenorphine is maximized.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/704,955, filed on May 5, 2015; which is a continuation of U.S. patentapplication Ser. No. 14/499,651, filed on Sep. 29, 2014; which is acontinuation of U.S. patent application Ser. No. 14/176,036, filed onFeb. 7, 2014; which is a continuation of U.S. patent application Ser.No. 13/590,094, filed on Aug. 20, 2012, now U.S. Pat. No. 8,703,177,issued on Apr. 22, 2014; which claims priority to U.S. ProvisionalApplication No. 61/525,094, filed on Aug. 18, 2011. This application isalso related to U.S. patent application Ser. No. 08/734,519, filed onOct. 18, 1996, now U.S. Pat. No. 5,800,832, issued on Sep. 1, 1998; U.S.patent application Ser. No. 11/639,408, filed on Dec. 13, 2006; U.S.patent application Ser. No. 11/817,915, filed on Sep. 6, 2007; and U.S.patent application Ser. No. 13/184,306, filed on Jul. 15, 2011, now U.S.Pat. No. 8,147,866, issued on Apr. 3, 2012. The entire contents of eachof the foregoing applications are incorporated herein by reference.

BACKGROUND

Buprenorphine is a partial μ-opiate receptor agonist, an ORL1/nociceptinreceptor agonist with high affinity, and slow association anddissociation from the receptors, and a κ-opiate receptor antagonist.Transmucosal bioavailability of buprenorphine is greater than its oralbioavailability, and, as a result, buprenorphine has been initiallydeveloped and marketed as a sublingual dosage form. Buprenorphine hasbeen generally available as Temgesic® 0.2 mg sublingual tablets and asBuprenex® in a 0.3 mg/ml parenteral formulation, both indicated for thetreatment of moderate to severe pain.

Because there is some risk of abuse with buprenorphine, particularly inthe doses used for opioid dependence, a combination product withnaloxone, an opioid antagonist, has been developed. The addition ofnaloxone to buprenorphine decreases the parenteral abuse potential ofbuprenorphine in opioid dependent subjects, as injected naloxoneprecipitates withdrawal by displacing the non-buprenorphine opioid fromthe receptor sites and blocking those sites from buprenorphineoccupancy. Human laboratory studies have been conducted to testdifferent dosage ratios of buprenorphine and naloxone (Fudala P. J. etal., Effects of buprenorphine and naloxone in morphine-stabilized opioidaddicts, (1998) Drug Alcohol Depend., 50(1):1-8; Mendelson J. et al.,Buprenorphine and naloxone combinations: the effects of three doseratios in morphine-stabilized, opiate-dependent volunteers, (1999)Psychopharmacology 141:37-46) and have led to the conclusion that aformulation comprising buprenorphine and naloxone at the dose ratio ofw/w 2:1 or 4:1 should be optimal for providing deterrence for opiateabusers. Suboxone® a sublingual pill preparation of buprenorphine thatcontains buprenorphine and naloxone at a 4:1 w/w dose ratio, and hasbeen approved by the FDA for treating opioid dependence.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of exemplary embodiments of thepresent invention.

FIG. 2 is a graph showing assessment of dose-proportionality ofbuprenorphine C_(max) after administration of the devices of theinvention containing 0.875/0.15 mg, 3.5/0.6 mg and 5.25/0.9 mg ofbuprenorphine/naloxone as described in Example 4.

FIG. 3 is a graph showing assessment of dose-proportionality ofbuprenorphine AUC_(inf) after administration of the devices of theinvention containing 0.875/0.15 mg, 3.5/0.6 mg and 5.25/0.9 mg ofbuprenorphine/naloxone as described in Example 4.

FIG. 4 is a graph showing COWS total scores recorded within 1 hour ofsubjects receiving study medication as a part of Naloxone WithdrawalStudy as described in Example 5.

FIG. 5 is a graph showing changes in blood pressure, heart rate andoxygen saturation in subjects receiving study medication as a part ofNaloxone Withdrawal Study as described in Example 5.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery thatbioavailability of an opioid agonist, e.g., buprenorphine, disposed inthe mucoadhesive layer of a two-layered, abuse-resistant transmucosaldrug delivery device is not only affected by the pH of the mucoadhesivelayer, but is also affected by the pH of the backing layer that resideson the lingual side of the bi-layer film. This layer may or may notcontain an opioid antagonist, however in the preferred embodiment of thecomposition of the backing layer, it does include an opioid antagonistsuch as naloxone. Accordingly, both the pH of the mucoadhesive layer andthe pH of the backing layer may be chosen such that the absorption ofbuprenorphine from the mucoadhesive layer is similar or higher thanabsorption from the mucoadhesive layer of a device with an unbufferedbacking layer, while the absorption of naloxone, if present in thebacking layer, is impeded.

The present invention is also based, at least in part, on the surprisingdiscovery, that the mucoadhesive devices with buffered backing layer maycomprise smaller doses of naloxone, while still providing abusedeterrence. The dose of naloxone is lowered, such that the w/wbuprenorphine to naloxone ratio is higher than the ratio of 4:1,accepted in the art as being effective for providing abuse deterrence.In some embodiments, the w/w buprenorphine to naloxone ratio present inthe mucoadhesive device of the invention is between 4:1 and 10:1. In aspecific embodiment, the w/w buprenorphine to naloxone ratio is 6:1.Such a device is advantageous because it can provide effective abusedeterrence at a lower naloxone dose.

This invention does not purport the need for naloxone in the backinglayer. In some embodiments, the amount of naloxone required toprecipitate withdrawal is as low as 0.1 mg when abused by injection. Insome embodiments, the maximum ratio of buprenorphine dose to naloxone is10:1 and can be as low at 1:1. In some embodiments, the ratio ofbuprenorphine dose to naloxone is 10:1 to 4:1. In a specific embodiment,the ratio is 6:1.

In some embodiments, the present invention provides an abuse deterrentmucoadhesive device for use in managing pain or opioid dependence, thedevice comprising:

-   -   a mucoadhesive layer comprising buprenorphine buffered to a pH        of between about 4.0 and about 6.0; and    -   a backing layer buffered to a pH between about 4.0 and about        4.8.

In some embodiments, the absorption of buprenorphine through the oralmucosal membrane is optimized and a therapeutically effective dose ofbuprenorphine is provided. In some embodiments, the backing layercomprises naloxone. In some embodiments, the w/w ratio of buprenorphineto naloxone present in the device is between 1:1 and 10:1. In someembodiments, the ratio is between about 4:1 and 10:1. In a preferredembodiment, the w/w ratio of buprenorphine to naloxone present in thedevice is 6:1.

In some embodiments, the present invention provides an abuse deterrentmucoadhesive device for use in managing pain or opioid dependence, thedevice comprising:

-   -   a mucoadhesive layer comprising buprenorphine buffered to a pH        of between about 4.0 and about 6.0;    -   and a backing layer buffered to a pH between about 4.0 and about        4.8;

wherein bioavailability of buprenorphine absorbed from the device isgreater than 40%. In some embodiments, the bioavailability is about 60%.In some embodiments, the bioavailability is about 65%. In someembodiments, the bioavailability is about 75%.

In some embodiments, the mucoadhesive layer is buffered to a pH ofbetween about 4.50 and about 5.50 and the backing layer is buffered to apH of between about 4.10 and about 4.4. In a preferred embodiment, themucoadhesive layer is buffered to a pH of about 4.75 and the backinglayer is buffered to a pH of about 4.25.

In some embodiments, the device comprises about 0.075-12 mg ofbuprenorphine. In some embodiments, the amount of buprenorphine is0.15-12 mg of buprenorphine. In some embodiments, the device alsocomprises about 0.0125-2 mg of naloxone. In some embodiments, the amountof naloxone is about 0.1-2 mg. In some embodiments, the bioavailabilityof buprenorphine absorbed from the device is greater than 40%.

In some embodiments, the present invention provides an abuse deterrentmucoadhesive device for use in managing pain or opioid dependence, thedevice comprising:

-   -   a mucoadhesive layer comprising buprenorphine and buffered to a        first pH;    -   a backing layer buffered to a second pH;    -   the second pH selected such that the transmucosal delivery of        buprenorphine is not impeded, such that the bioavailability of        buprenophine is greater than 40%. In some embodiments, the        backing layer comprises naloxone, and the delivery of naloxone        is impeded.

In some embodiments, the invention also provides an abuse deterrentmucoadhesive device for use in managing pain or opioid dependence, thedevice comprising:

-   -   a mucoadhesive layer comprising buprenorphine and buffered to a        first pH,    -   a backing layer buffered to a second pH,    -   the first pH and the second pH selected such that the        unidirectional delivery gradient of buprenorphine toward the        mucosa is not impeded, such that the total bioavailability of        buprenophine provided by the device is similar to the total        bioavailability of buprenorphine provided by the same device        wherein the pH of the backing layer is not adjusted. In one        embodiment, the backing layer comprises naloxone, and the        delivery of naloxone is impeded.

In some embodiments, an abuse deterrent mucoadhesive device for use inmanaging pain or opioid dependence comprises:

-   -   a mucoadhesive layer comprising buprenorphine and buffered to a        first pH and a backing layer buffered to a second pH;        -   wherein the first pH is between about 4.0 and about 6.0;        -   wherein the second pH is between about 4.0 and about 4.8.

In some embodiments, the backing layer comprises naloxone. In someembodiments, buprenorphine and naloxone disposed in the device arepresent in w/w ratio of about 4:1 to about 10:1 ofbuprenorphine:naloxone. In one embodiment, the ratio is about 6:1.

In some embodiments, the first pH is between about 4.50 and about 5.50and the second pH is between about 4.10 and about 4.4. In a specificembodiment, the first pH is about 4.75 and the second pH is about 4.25.In some embodiments, the device comprises about 0.075 to 12 mg ofbuprenorphine and about 0.0125-2 mg of naloxone.

In some embodiments, an abuse deterrent mucoadhesive device for use inmanaging pain or opioid dependence comprises:

-   -   a mucoadhesive layer comprising buprenorphine and buffered to a        first pH and a backing layer buffered to a second pH;        -   wherein the first pH is between about 4.0 and about 6.0;        -   wherein the second pH is between about 4.0 and about 4.8;            and        -   wherein bioavailability of buprenorphine absorbed from the            device is greater than 40%. In some embodiments, the backing            layer comprises naloxone.

In some embodiments, the first pH is between about 4.50 and about 5.50and the second pH is between about 4.10 and about 4.4. In a specificembodiment, the first pH is about 4.75 and the second pH is about 4.25.In some embodiments, the device comprises about 0.075 to 12 mg ofbuprenorphine and about 0.0125-2 mg of naloxone.

In a preferred embodiment, the abuse deterrent mucoadhesive device foruse in managing pain or opioid dependence comprises:

-   -   a mucoadhesive layer comprising buprenorphine and buffered to a        first pH and a backing layer comprising naloxone and buffered to        a second pH;        -   wherein the first pH is about 4.75;        -   wherein the second pH is about 4.25; and        -   wherein buprenorphine and naloxone disposed in the device            are present in w/w ratio of about 6:1 of            buprenorphine:naloxone.

In some embodiments, methods of treating pain or managing opioiddependence in a subject are also provided. The methods generallycomprise administering to a subject in need thereof an abuse deterrentmucoadhesive device of the invention, such that pain is treated oropioid dependence is managed in a subject.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are provided as guidance as to the meaning ofcertain terms used herein.

As used herein, the articles “a” and “an” mean “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement of the present invention by the indefinite article “a” or “an”does not exclude the possibility that more than one of the element ispresent.

As used herein, the term “absorption” refers to the process of asubstance, such as a drug, entering the bloodstream. Absorption can bemeasured by pharmacokinetic parameters, such as AUC_(inf) and C_(max).

As used herein, the term “acute pain” refers to pain characterized by ashort duration, e.g., three to six months. Acute pain is typicallyassociated with tissue damage, and manifests in ways that can be easilydescribed and observed. It can, for example, cause sweating or increasedheart rate. Acute pain can also increase over time, and/or occurintermittently.

As used herein, the term “bioavailability” is as defined in 21 CFRSection 320.1 and refers to the rate and extent to which the activeingredient or active moiety is absorbed from a drug product and becomesavailable at the site of action. The term “bioavailable,” “absolutebioavailability” or “total bioavailability” refers to the totalbioavailability including amounts that are transmitted via the mucosalmembrane (i.e., transmucosally) and through the GI tract. The term“absolute bioavailability” refers to a fraction of a drug absorbedthrough non-intravenous administration (i.e., transmucosal, oral,rectal, transdermal, subcutaneous, or sublingual administration)compared with the bioavailability of the same drug following intravenousadministration. The comparison is dose normalized, i.e., accounts fordifferent doses consequently, the amount absorbed is corrected bydividing the corresponding dose administered. In some embodiments, themucoadhesive devices of the present invention provide absolutebioavailability of the opioid agonist buprenorphine that is equal to orgreater than 40%, e.g., 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%,49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%,63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

As used herein, the term “bioequivalence” or “bioequivalent” is asdefined in 21 CFR Section 320.1, and means the absence of a significantdifference in the rate and extent of absorption of an active ingredientor active moiety in one pharmaceutical product and another. Forbioequivalence, the pharmacokinetic parameters C_(max) and AUC forbioequivalent actives fall within the 80%-125% range of each other. Insome embodiments, the devices of the present invention may bebioequivalent to Suboxone® sublingual tablet. Pharmacokineticparameters, e.g., C_(max) and AUC_(inf), for Suboxone® sublingualtablets comprising 2.0/0.5 mg and 8.0/2.0 mg of buprenorphine/naloxoneis contained in the product label for Suboxone®, which is incorporatedherein by reference in its entirety.

As used herein, the term “chronic pain” refers to pain which persistsbeyond the usual recovery period for an injury or illness. Chronic paincan be constant or intermittent. Common causes of chronic pain include,but are not limited to, arthritis, cancer, Reflex Sympathetic DystrophySyndrome (RSDS), repetitive stress injuries, shingles, headaches,fibromyalgia, and diabetic neuropathy, lower back pain, neck andshoulder pain, moderate to severe osteoarthritis, and patients withsevere migraine.

As used herein, unless indicated otherwise, the term “buprenorphine”,includes any pharmaceutically acceptable form of buprenorphine,including, but not limited to, salts, esters, and prodrugs thereof. Inone embodiment, the term “buprenorphine” refers to buprenorphinehydrochloride. As used herein, the term “buprenorphine derivative”refers to compounds having similar structure and function tobuprenorphine. In some embodiments, buprenorphine derivatives includethose of the following formula:

or pharmaceutically acceptable salts or esters thereof, wherein

is a double or single bond; R₃ is selected from a —C₁₋₄ alkyl group or acycloalkyl-substituted-C₁₋₄ alkyl group; R₄ is selected from a —C₁₋₄alkyl; R₅ is —OH, or taken together, R₄ and R₅ form a ═O group; and R₆is selected from —H or a —C₁₋₄ alkyl group.

Buprenorphine derivatives include, but are not limited to, etorphine anddiprenorphine. General buprenorphine derivatives are described in WO2008/011194, which is hereby incorporated by reference.

As used herein, unless indicated otherwise, the term “naloxone” includesany pharmaceutically acceptable form of naloxone, including, but notlimited to, salts, esters, and prodrugs thereof. In one embodiment, theterm “naloxone” refers to naloxone hydrochloride. In some embodiments,naloxone is represented by the following chemical structure:

As used herein, the term “mucoadhesive layer” or “polymeric diffusionenvironment” refers to an environment capable of allowing flux of amedicament to a mucosal surface upon creation of a gradient by adhesionof the polymeric diffusion environment to a mucosal surface. The flux ofa transported medicament is proportionally related to the diffusivity ofthe environment which can be manipulated by, e.g., adjusting the pH,taking into account the ionic nature of the medicament and/or the ionicnature of the polymer or polymers included in the environment.

As used herein, the term “backing layer” or “non-adhesive polymericenvironment” refers to an environment in the form of, e.g., a layer orcoating or barrier layer, capable of slowing, reducing or stopping fluxof a medicament in its direction and does not adhere to surfaces in theoral cavity. In some embodiments, the pH of the backing layer isadjusted, such as it stops flux of a medicament contained therein and inthe mucoadhesive layer, except in the direction of the mucosa. In someembodiments, the non-adhesive polymeric environment significantly slowsflux of a medicament, e.g., enough so that little or no medicament iswashed away by saliva. In some embodiments, the non-adhesive polymericenvironment slows or stops flux of a medicament, while allowinghydration of the polymeric diffusion environment e.g., by saliva.

As used herein, the term “unidirectional gradient” refers to a gradientwhich allows for the flux of a medicament (e.g., buprenorphine) throughthe device, e.g., through a polymeric diffusion environment, insubstantially one direction, e.g., to the mucosa of a subject. Forexample, the polymeric diffusion environment may be a mucoadhesivepolymeric diffusion environment in the form of a layer or film disposedadjacent to a backing layer or film. Upon mucosal administration, agradient is created between the mucoadhesive polymeric diffusionenvironment and the mucosa, and the medicament flows from themucoadhesive polymeric diffusion environment, substantially in onedirection towards the mucosa. In some embodiments, some flux of themedicament is not entirely unidirectional across the gradient; however,there is typically not free flux of the medicament in all directions.

As used herein, “treating” or “treatment” of a subject includes theadministration of a drug to a subject with the purpose of preventing,curing, healing, alleviating, relieving, altering, remedying,ameliorating, improving, stabilizing or affecting a disease or disorder,or a symptom of a disease or disorder (e.g., to alleviate pain).

The term “subject” refers to living organisms such as humans, dogs,cats, and other mammals. Administration of the medicaments included inthe devices of the present invention can be carried out at dosages andfor periods of time effective for treatment of a subject. In someembodiments, the subject is a human. In some embodiments, thepharmacokinetic profiles of the devices of the present invention aresimilar for male and female subjects.

An “effective amount” of a drug necessary to achieve a therapeuticeffect may vary according to factors such as the age, sex, and weight ofthe subject. Dosage regimens can be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation.

The term “transmucosal,” as used herein, refers to any route ofadministration via a mucosal membrane. Examples include, but are notlimited to, buccal, sublingual, nasal, vaginal, and rectal. In oneembodiment, the administration is buccal. In one embodiment, theadministration is sublingual. As used herein, the term “directtransmucosal” refers to mucosal administration via the oral mucosa,e.g., buccal and/or sublingual.

As used herein, the term “water erodable” or “at least partially watererodable” refers to a substance that exhibits a water erodabilityranging from negligible to completely water erodable. The substance mayreadily dissolve in water or may only partially dissolve in water withdifficulty over a long period of time. Furthermore, the substance mayexhibit a differing erodability in body fluids compared with waterbecause of the more complex nature of body fluids. For example, asubstance that is negligibly erodable in water may show an erodabilityin body fluids that is slight to moderate. However, in other instances,the erodability in water and body fluid may be approximately the same.

The term “impeded” when used to describe the absorption or the deliveryof the opioid antagonist from the abuse-resistant device refers to theabsorption and/or delivery of said opioid antagonist that isinsufficient to inhibit the effects of the opioid agonist comprised inthe same device.

As used herein, “addiction therapy” as related to a subject includes theadministration of a drug to a subject with the purpose of reducing thecravings for the addictive substance.

As used herein, the term “abusive” or “abusive manner” refers to uses ofthe devices beyond transmucosal administration such as by injecting orsnorting.

As used herein, the term “disposed” refers to the uniform or non-uniformdistribution of an element within another.

Maintenance Treatment of Opioid Dependence

Certain aspects of the present invention include methods for providingmaintenance treatment for a subject addicted to opioids. Presently,buprenorphine maintenance is one of the most promising courses of actionfor addicted subjects in terms of long-term abstinence.

Pain Management

Certain aspects of the present invention include methods for providingpain management and/or relief to a subject in need thereof. The pain canbe any pain known in the art, caused by any disease, disorder, conditionand/or circumstance and can be chronic pain or acute pain.

Transmucosal Mucoadhesive Pharmaceutical Delivery Device

In certain aspects of the present invention, abuse-resistanttransmucosal delivery devices are provided. Accordingly, in oneembodiment, the present invention is directed to abuse-resistantmucoadhesive delivery devices suitable for administration of aneffective amount of an opioid drug to a subject, for the management ofpain and/or opioid dependence. The device is capable of delivering theopioid agonist by means of a unidirectional gradient (i.e. flux thatflows toward the mucosa) that is created upon application of the deviceto a mucosal surface.

The devices of the present invention can include any combination orsub-combination of ingredients, layers and/or compositions of, e.g., thedevices described in U.S. Pat. No. 6,159,498, U.S. Pat. No. 5,800,832,U.S. Pat. No. 6,585,997, U.S. Pat. No. 6,200,604, U.S. Pat. No.6,759,059 and/or PCT Publication No. WO 05/06321. The contents of thesepatent and publications are incorporated herein by reference in theirentireties.

i. Mucoadhesive Layer

In some embodiments, the mucoadhesive layer is a bioerodable orwater-erodable mucoadhesive layer. In some embodiments, the devices ofthe present invention include a bioerodable mucoadhesive layer whichcomprises a mucoadhesive polymeric diffusion environment. The deviceadheres to a mucosal surface of the subject within about 5 secondsfollowing application.

In some embodiments, the mucoadhesive polymeric diffusion environmentcomprises an opioid agonist. In some embodiments, the opioid agonist isbuprenorphine. In some embodiments related to the treatment of opioiddependence, the dose of buprenorphine that can be incorporated into thedevice of the present invention depends on the desired treatment dosageto be administered and can range from about 10 μg to about 20 mg ofbuprenorphine. In other embodiments related to the treatment of pain,the dose of buprenorphine can range from about 60 μg to about 6 mg. Insome embodiments, the low dose of buprenorphine comprised in themucoadhesive device of the invention is between about 0.075 and 12 mg ofbuprenorphine, e.g., 0.075 mg, 0.080 mg, 0.085 mg, 0.090 mg, 0.095 mg,0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.40 mg, 0.45 mg,0.50 mg, 0.44 mg, 0.60 mg, 0.65 mg, 0.70 mg, 0.75 mg, 0.80 mg, 0.85 mg,0.90 mg, 0.95 mg, 1.00 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.25 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mgor 12.0 mg or buprenorphine. In one embodiment, the dose is 0.875 mg ofbuprenorphine. In another embodiment, the dose is 1.75 mg ofbuprenorphine. In another embodiment, the dose is 3.5 mg ofbuprenorphine. In yet another embodiment, the dose is 5.25 mg ofbuprenorphine.

In some embodiments, the mucoadhesive polymeric diffusion environmentcan include the drug, at least one pharmacologically acceptable polymercapable of bioadhesion (the “bioadhesive polymer”), and can optionallyinclude at least one film-forming bioerodable or water-erodable polymer(the “film-forming polymer”). Alternatively, the mucoadhesive polymericdiffusion environment can be formed of a single polymer that acts asboth the bioadhesive polymer and the first film-forming polymer.Additionally or alternatively, the mucoadhesive polymeric diffusionenvironment can include other film-forming water-erodable polymersand/or water-erodable plasticizers, such as glycerin and/or polyethyleneglycol (PEG).

In some embodiments, the bioadhesive polymer of the mucoadhesivepolymeric diffusion environment can include any water erodablesubstituted cellulosic polymer or substituted olefinic polymer whereinthe substituents may be ionic or hydrogen bonding, such as carboxylicacid groups, hydroxyl alkyl groups, amine groups and amide groups. Forhydroxyl containing cellulosic polymers, a combination of alkyl andhydroxyalkyl groups will be preferred for provision of the bioadhesivecharacter and the ratio of these two groups will have an effect uponwater swellability and dispersability. Examples include polyacrylic acid(PAA), which can optionally be partially cross-linked, sodiumcarboxymethyl cellulose (NaCMC), moderately to highly substitutedhydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP3 whichcan optionally be partially cross-linked), moderately to highlysubstituted hydroxyethylmethyl cellulose (HEMC) or combinations thereof.In one embodiment, HEMC can be used as the bioadhesive polymer and thefirst film forming polymer as described above for a mucoadhesivepolymeric diffusion environment formed of one polymer. These bioadhesivepolymers are preferred because they have good and instantaneousmucoadhesive properties in a dry, system state.

In some embodiments, the mucoadhesive polymeric diffusion environment,e.g., a bioerodable mucoadhesive layer, is generally comprised ofwater-erodable polymers which include, but are not limited to,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl cellulose(HEMC), polyacrylic acid (PAA) which may or may not be partiallycross-linked, sodium carboxymethyl cellulose (NaCMC), andpolyvinylpyrrolidone (PVP), or combinations thereof. Other mucoadhesivewater-erodable polymers may also be used in the present invention. Theterm “polyacrylic acid” includes both uncross-linked and partiallycross-linked forms, e.g., polycarbophil.

Similar film-forming water-erodable polymers can also be used. Thefilm-forming water-erodable polymers can optionally be cross-linkedand/or plasticized in order to alter its dissolution kinetics.

In some embodiments, the properties of the mucoadhesive polymericdiffusion environment are influenced by its pH. In some embodiments,e.g., when mucoadhesive polymeric diffusion environment comprisesbuprenorphine, its pH is between about 4.0 and about 7.5. In oneembodiment, the pH is between 4.0 and 6.0, more specifically, between4.5 and 5.5, and even more specifically, between 4.75 and 5.25. In aspecific embodiment, the pH is 4.75. It is to be understood that allvalues and ranges between these values and ranges are meant to beencompassed by the present invention.

The pH of the mucoadhesive polymeric diffusion environment can beadjusted and/or maintained by methods including, but not limited to, theuse of buffering agents, or by adjusting the composition of the deviceof the present invention.

Buffering agents suitable for use with the present invention include,for example, phosphates, such as sodium phosphate; phosphates monobasic,such as sodium dihydrogen phosphate and potassium dihydrogen phosphate;phosphates dibasic, such as disodium hydrogen phosphate and dipotassiumhydrogen phosphate; phosphates tribasic, such as trisodium phosphate;citrates, such as sodium citrate (anhydrous or dehydrate) and triethylcitrate; bicarbonates, such as sodium bicarbonate and potassiumbicarbonate; acetates, such as sodium acetate, may be used. In oneembodiment, a single buffering agent, e.g., a dibasic buffering agent isused. In another embodiment, a combination of buffering agents isemployed, e.g., a combination of a tri-basic buffering agent and amonobasic buffering agent. In some embodiments, the amount of bufferingagent is present in a composition used to make the mucoadhesive layer isabout 1 to 20% of the amount of the agonist drug, e.g., buprenorphine.ii. Backing Layer

The device further comprises at least one additional non-adhesivepolymeric environment, e.g., a backing layer. This layer is disposedadjacent to the mucoadhesive polymeric diffusion environment, e.g., abacking layer, functions to facilitate the delivery of the opioidagonist, such as buprenorphine, to the mucosa. This additional layer maycomprise the same or a different combination of polymers as themucoadhesive polymeric diffusion environment or the non-adhesivepolymeric diffusion environment.

In some embodiments, the backing layer includes an additionalmedicament, such as an opioid antagonist, to render the device of theinvention abuse-resistant. In some embodiments, the opioid antagonist isnaloxone. The dose of naloxone that can be incorporated into the deviceof the present invention depends on the desired treatment dosage to beadministered and can range from about 100 μg to 5 mg of naloxone for thetreatment of dependence, and from 60 μg to 1.5 mg naloxone for the painindication. In some embodiments, the dose of naloxone is between about0.0125 mg to about 2.0 mg of naloxone, e.g., 0.0125 mg, 0.0130 mg,0.0135 mg, 0.0140 mg, 0.0145 mg, 0.0150 mg, 0.0155 mg, 0.0160 mg, 0.0165mg, 0.0170 mg, 0.0175 mg, 0.0180 mg, 0.0185 mg, 0.0190 mg, 0.0195 mg,0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg,0.1 mg, 0.145 mg, 0.2 mg, 0.29 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.58 mg, 0.6mg, 0.7 mg, 0.8 mg, 0.87 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg or 2.0 mg of naloxone. In oneembodiment, the dose is 0.145 mg of naloxone. In another embodiment, thedose is 290 μg of naloxone. In another embodiment, the dose is 580 μg ofnaloxone. In yet another embodiment, the dose is 870 μg of naloxone. Insome embodiments, the amount of buprenorphine and the amount of naloxonedisposed in the device are present in a ratio chosen such that theeffect of buprenorphine is negated by naloxone if the mixture isinjected or snorted. In such embodiment, buprenorphine and naloxonedisposed in the device are present in a w/w ratio that ranges between1:4 and 1:10. In a preferred embodiment, the w/w ratio of buprenorphineto naloxone is 1:4 to 1:6, wherein 1:6 is the most preferred embodiment.

In some embodiments, the backing layer (i.e., the non-adhesive polymericembodiment) functions as a barrier to facilitate a unidirectional fluxof the medicament, e.g., buprenorphine, disposed in the mucoadhesivelayer. Upon application to a mucosal surface, a diffusional gradient ofa medicament is created towards the mucosa. In another embodiment thebacking layer, can serve an erodible polymer that facilitate absorptionof buprenorphine in the orophyrangeal tissue. In some embodiments,prevents diffusion away from the mucosal surface. In such instances, amajority of the medicament, i.e., at least 50% flows towards the mucosa.In other embodiments, as depicted in FIG. 1, the non-adhesive polymericenvironment may circumscribe the boundaries of the mucoadhesivepolymeric diffusion environment thereby ensuring that medicament flowstoward the mucosa.

The backing layer (e.g., a water-erodable non-adhesive backing layer)can further include at least one water erodable, film-forming polymer.This layer may optionally include a drug. The polymer or polymers caninclude polyethers and polyalcohols as well as hydrogen bondingcellulosic polymers having either hydroxyalkyl group substitution orhydroxyalkyl group and alkyl group substitution preferably with amoderate to high ratio of hydroxyalkyl to alkyl group. Examples include,but are not limited to, hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC),hydroxyethylmethyl cellulose (HEMC), polyvinyl alcohol (PVA),polyethylene glycol (PEG), polyethylene oxide (PEO), ethyleneoxide-propylene oxide co polymers, ethylene oxide-propylene oxideco-polymers, and combinations thereof. The water-erodable non-adhesivebacking layer component can optionally be cross-linked.

In certain embodiments, the non-adhesive backing layer is free ofcross-linked polymers. In a preferred embodiment of the device, thenon-adhesive backing layer is free of polyacrylic acid. While notwishing to be bound by any specific theory, it is estimated that theresidence time is reduced by the absence of said polyacrylic acid. Forexample, in certain embodiments, the residence time is between 15 and 30minutes. In a preferred embodiment, the water erodable non-adhesivebacking layer includes hydroxyethyl cellulose and hydroxypropylcellulose.

The devices of the present invention can include ingredients that areemployed to, at least in part, provide a desired residence time. In someembodiments, this is a result of the selection of the appropriatebacking layer formulation, providing a slower rate of erosion of thebacking layer. Thus, the non-adhesive backing layer is further modifiedto render controlled erodability which can be accomplished by coatingthe backing layer film with a more hydrophobic polymer selected from agroup of FDA approved Eudragit™ polymers, ethyl cellulose, celluloseacetate phthalate, and hydroxyl propyl methyl cellulose phthalate, thatare approved for use in other pharmaceutical dosage forms. Otherhydrophobic polymers may be used, alone or in combination with otherhydrophobic or hydrophilic polymers, provided that the layer derivedfrom these polymers or combination of polymers erodes in a moistenvironment. Dissolution characteristics may be adjusted to modify theresidence time and the release profile of a drug when included in thebacking layer.

In some embodiments, any of the layers in the devices of the presentinvention may also contain a plasticizing agent, such as propyleneglycol, polyethylene glycol, or glycerin in a small amount, 0 to 15% byweight, in order to improve the “flexibility” of this layer in the mouthand to adjust the erosion rate of the device. In addition, humectantssuch as hyaluronic acid, glycolic acid, and other alpha hydroxyl acidscan also be added to improve the “softness” and “feel” of the device.Finally, colors and opacifiers may be added to help distinguish theresulting non-adhesive backing layer from the mucoadhesive polymericdiffusion environment. Some opacifers include titanium dioxide, zincoxide, zirconium silicate, etc.

The device can also optionally include a pharmaceutically acceptabledissolution-rate-modifying agent, a pharmaceutically acceptabledisintegration aid (e.g., polyethylene glycol, dextran, polycarbophil,carboxymethyl cellulose, or poloxamers), a pharmaceutically acceptableplasticizer, a pharmaceutically acceptable coloring agent (e.g., FD&CBlue #1), a pharmaceutically acceptable opacifier (e.g., titaniumdioxide), pharmaceutically acceptable anti-oxidant (e.g., tocopherolacetate), a pharmaceutically acceptable system forming enhancer (e.g.,polyvinyl alcohol or polyvinyl pyrrolidone), a pharmaceuticallyacceptable preservative, flavorants (e.g., saccharin and peppermint),neutralizing agents (e.g., sodium hydroxide), buffering agents (e.g.,monobasic, or tribasic sodium phosphate), or combinations thereof.Preferably, these components are individually present at no more thanabout 1% of the final weight of the device, but the amount may varydepending on the other components of the device.

In some embodiments, the non-adhesive polymeric diffusion environment,e.g., the backing layer, is a buffered environment. In some embodimentsthe pH of the backing layer is between 4.0 and 6.0, more specifically,between 4.2 and 4.7, and even more specifically, between 4.2 and 4.4. Inone embodiment, the pH of the backing layer is 4.25. It is to beunderstood that all values and ranges between these values and rangesare meant to be encompassed by the present invention.

The pH of the backing layer can be adjusted and/or maintained by methodsincluding, but not limited to, the use of buffering agents, or byadjusting the composition of the device of the present invention. Insome embodiments, the properties of the polymeric diffusion environmentare influenced by its buffering capacity. In some embodiments, bufferingagents are included in the mucoadhesive polymeric diffusion environment.Buffering agents suitable for use with the present invention include,for example, phosphates, such as sodium phosphate; phosphates monobasic,such as sodium dihydrogen phosphate and potassium dihydrogen phosphate;phosphates dibasic, such as disodium hydrogen phosphate and dipotassiumhydrogen phosphate; phosphates tribasic, such as trisodium phosphate;citrates, such as sodium citrate (anhydrous or dehydrate) and triethylcitrate; bicarbonates, such as sodium bicarbonate and potassiumbicarbonate; acetates, such as sodium acetate, may be used. In oneembodiment, a single buffering agent, e.g., a dibasic buffering agent isused. In another embodiment, a combination of buffering agents isemployed, e.g., a combination of a tri-basic buffering agent and amonobasic buffering agent. In some embodiments, the backing layercomprises the opioid antagonist. In another embodiment, the backinglayer comprises an opioid antagonist that is present as amicroencapsulated particle with polymers. These polymers include, butare not limited to alginates, polyethylene oxide, poly ethylene glycols,polylactide, polyglycolide, lactide-glycolide copolymers,poly-epsilon-caprolactone, polyorthoesters, polyanhydrides andderivatives, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropylmethyl cellulose, polyacrylic acid, and sodiumcarboxymethyl cellulose, poly vinyl acetate, poly vinyl alcohols,polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxideco-polymers, collagen and derivatives, gelatin, albumin, polyaminoacidsand derivatives, polyphosphazenes, polysaccharides and derivatives,chitin, chitosan bioadhesive polymers, polyacrylic acid, polyvinylpyrrolidone, sodium carboxymethyl cellulose and combinations thereof.

EXEMPLIFICATION OF THE INVENTION

The invention will be further understood by the following examples.However, those skilled in the art will readily appreciate that thespecific experimental details are only illustrative and are not meant tolimit the invention as described herein, which is defined by the claimswhich follow thereafter.

Example 1 Preparation of the Devices of the Invention

Several formulations were prepared comprising different doses ofbuprenorphine and naloxone, with the backing layers adjusted todifferent pHs, as described in the Table 1 below:

TABLE 1 Formulations of the invention Ratio of bupre- norphine For- pHpH Bupre- to mulation backing mucoadhesive norphine Naloxone naloxoneNo. layer layer (mg) (mg) (w/w) 1 2.8 4.75 0.75 0.1875 4:1 2 2.8 4.753.0 0.75 4:1 3 4.25 4.75 0.75 0.1875 4:1 4 4.25 4.75 3.0 0.75 4:1 5 4.254.75 0.875 0.15 6:1 6 4.25 4.75 3.5 0.6 6:1 7 4.25 4.75 5.25 0.875 6:1

The ingredients used to prepare the mucoadhesive layer for Formulations2, 4 and 6 are summarized in the Table 2 below:

TABLE 2 Ingredients for preparing the mucoadhesive layer at pH 4.75Amount (mg) Formulation 2 Formulation 4 Formulation 6 Ingredient 3.11cm² film 3.11 cm² film 3.58 cm² film Purified Water ConstitutesConstitutes Constitutes 88.911% 88.911% 88.911% w/w of the w/w of thew/w of the wet blend wet blend wet blend Propylene Glycol 0.704 0.7040.822 Sodium Benzoate 0.082 0.082 0.095 Methylparaben 0.137 0.137 0.160Propylparaben 0.038 0.038 0.045 Yellow Ferric Oxide 0.082 0.082 0.095Citric Acid, 0.082 0.082 0.096 Anhydrous Vitamin E Acetate 0.008 0.0080.010 Monobasic Sodium 0.521 0.520 0.607 Phosphate, AnhydrousBuprenorphine HCl 3.234 3.234 3.773 Polycarbophil 0.980 0.979 1.143Hydroxypropyl 1.051 1.051 1.226 Cellulose Hydroxyethyl 3.144 3.143 3.668Cellulose Carboxymethyl- 8.399 8.398 9.799 cellulose Sodium SodiumHydroxide 0.043 0.043 0.051

The mucoadhesive layer for Formulations 1 and 3 is prepared using thesame ingredients as for formulations 2 and 4, respectively, except thatthe amounts of all ingredients are adjusted in direct proportion to theamount of buprenorphine and the film size of 0.78 cm². Similarly, themucoadhesive layer for Formulations 5 and 7 are prepared using the sameingredients as for Formulation 6, except that the amounts of allingredients are adjusted in direct proportion to the amount ofbuprenorphine and film size of 0.9 cm² for formulation 5 and 5.37 cm²for Formulation 7.

The ingredients used to prepare the backing layer in Formulation 2 aresummarized in the Table 3 below:

TABLE 3 Ingredients for preparing the backing layer at pH 2.8 and 4.25Amount (mg) Formulation 2 Formulation 4 Formulation 6 Ingredient 3.11cm² film 3.11 cm² film 3.58 cm² film Purified Water ConstitutesConstitutes Constitutes 88.911% 88.911% 88.911% w/w of the w/w of thew/w of the wet blend wet blend wet blend Hydroxypropyl — 46.337 56.164Cellulose Hydroxyethyl 65.182 22.920 27.740 Cellulose Sodium Benzoate0.296 0.371 0.449 Methylparaben 0.296 0.337 0.408 Propylparaben 0.0740.067 0.082 Dibasic Sodium — 0.167 0.203 Phosphate Citric acid, 2.9550.412 0.498 anhydrous Vitamin E acetate 0.030 0.034 0.041 SaccharinSodium 1.786 1.416 0.054 Yellow Ferric 0.057 0.044 1.751 Oxide TriethylCitrate 3.774 — — Citrus Flavor — 1.989 2.409 Peppermint Oil 0.608 — —Naloxone HCl 0.916 0.916 0.733

The backing layer for Formulations 1 and 3 is prepared using the sameingredients as for Formulations 2 and 4, respectively, except that theamounts of all ingredients are adjusted in direct proportion to theamount of naloxone and the film size of 0.78 cm². Similarly, the backinglayer for Formulations 5 and 7 is prepared using the same ingredients asfor Formulation 6, except that the amounts of all ingredients areadjusted in direct proportion to the amount of buprenorphine and filmsize of 0.9 cm² for Formulation 5 and 5.37 cm² for Formulation 7.

Example 2 Absorption Profiles for Formulations 1 and 2

This was an open label, active controlled study in healthy subjects inorder to compare pharmacokinetic parameters of buprenorphine andnaxolone from formulations 1 and 2 with Suboxone® sublingual tablets.Blood samples for analysis were collected pre-dose and at 0.5, 1, 1.5,2, 3, 4, 6, 8, 12 and 16 hours post-dose and analyzed using theestablished procedures utilizing liquid chromatography and massspectrometry (LC/MS). The selected pharmacokinetic parameters forbuprenorphine and total naloxone are shown in Table 4.

TABLE 4 Selected Pharmacokinetic Parameters for Buprenorphine and TotalNaloxone for low dose formulations. Formulation 1 (0.75 mgbuprenorphine/ Suboxone ® 0.1875 mg naloxone, (2.0 mg buprenorphine/Pharmaco- backing layer at pH 2.8) 0.5 mg naloxone) kinetic- Total TotalParameter Buprenorphine Naloxone Buprenorphine Naloxone Mean T_(max)(hr) 2.29 1.29 1.75 0.92 Mean C_(max) 0.564 2.24 1.28 5.88 (ng/mL) MeanAUC_(last) 3.379 4.021 9.177 12.38 (hr * ng/mL) Mean AUC_(inf) 3.8684.585 10.92 13.26 (hr * ng/mL) Mean T_(1/2) 10.72 2.58 23.72 4.15Absolute 46% — 25%¹ — Bioavailability ¹Roy, S. D. et al., Transdermaldelivery of buprenorphine through cadaver skin (1994), J. Pharm. Sci.,83:126-130.

The results indicate that C_(max) and AUC_(inf) values for buprenorphineand total naloxone from Formulation 1 are less than the values observedfrom the control Suboxone® tablets.

Example 3 Absorption Profiles for Formulations 3 and 4

This study was designed to compare the plasma pharmacokinetic parametersof buprenorphine and naxolone from formulations 3 and 4 with Suboxone®sublingual tablets. This was a single dose, 2-period, crossover designwith 24 subjects randomized to one of two, 12-subject groups. Each groupreceived the device of the invention and Suboxone® tablets in randomsequence, each separated by at least 5 days. Group 1 subjects received asingle low dose Suboxone® tablet (containing 2.0 mg of buprenorphine and0.5 mg of naloxone) and a single dose of formulation 3. Group 2 subjectsreceived a single high dose Suboxone® tablet (containing 8.0 mg ofbuprenorphine and 2.0 mg of naloxone) and a single dose of formulation4. Naltrexone was co-administered approximately 12 hours and 30 minutesprior to and approximately 12 and 24 hours after the single study drugdoses. Serial blood samples for pharmacokinetic analyses were collectedpre-dose and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 210,240, 270, 300, 330 and 360 minutes post-dose and at 8, 10, 12, 24 and 48hours post-dose. Blood samples were analyzed using the establishedprocedures utilizing liquid chromatography and mass spectrometry(LC/MS). The selected pharmacokinetic parameters for buprenorphine andfree naloxone are shown in Tables 6 and 7.

TABLE 6 Selected Pharmacokinetic Parameters for Buprenorphine and FreeNaloxone for low dose formulations Formulation 3 (0.75 mgbuprenorphine/0.1875 mg Suboxone ® naloxone, backing (2.0 mgbuprenorphine/ Pharmaco- layer at pH 4.25) 0.5 mg naloxone) kinetic FreeFree Parameter Buprenorphine Naloxone Buprenorphine Naloxone MeanT_(max) (hr) 2.11 1.17 1.8 0.85 Mean C_(max) 1.10 0.0528 0.853 0.0441(ng/mL) Mean AUC_(last) 5.325 0.1297 6.321 0.1151 (hr * ng/mL) MeanAUC_(inf) 5.938 0.1346 7.339 0.1208 (hr * ng/mL) Mean T_(1/2) 10.10 1.2220.33 2.06 Absolute 75% — 25% — Bioavailability

TABLE 7 Selected Pharmacokinetic Parameters for Buprenorphine and FreeNaloxone for high dose formulations Formulation 4 (3.0 mgbuprenorphine/0.75 mg Suboxone ® naloxone, backing (8.0 mgbuprenorphine/ Pharmaco- layer at pH 4.25) 2.0 mg naloxone) kinetic FreeFree Parameter Buprenorphine Naloxone Buprenorphine Naloxone MeanT_(max) (hr) 2.17 1.05 1.70 0.92 Mean C_(max) 3.44 0.233 3.21 0.152(ng/mL) Mean AUC_(last) 19.46 0.5815 23.05 0.4529 (hr * ng/mL) MeanAUC_(inf) 21.50 0.5884 29.76 0.471 (hr * ng/mL) Mean T_(1/2) 18.82 2.8029.21 6.33 Absolute 65% — 25% — Bioavailability

The results indicate that, unexpectedly, the absorption of buprenorphinefrom Formulations 3 and 4 are increased, as compared to control. Thisincrease in buprenorphine absorption is particularly surprising in viewof the results of Example 2 and is caused by the change of pH of thebacking layer from 2.8 in Formulations 1 and 2 to 4.25 in Formulations 3and 4.

The results also indicate that C_(max) values for buprenorphine fromFormulations 3 and 4 are comparable to values from the control Suboxone®tablets and that the AUC_(inf) values for buprenorphine from the devicesof the invention are slightly less than the values from thecorresponding Suboxone® tablets. Further, the C_(max) and AUC_(inf)values for free (unconjugated) naloxone are greater than the values fromthe corresponding Suboxone® tablets.

Example 4 Absorption Profiles for Formulations 5, 6 and 7

This study was designed to assess the plasma pharmacokinetic parametersfor buprenorphine and naloxone exposure following administration ofFormulations 5, 6 and 7 comprising buprenorphine and naloxone present atthe w/w ratio of 6:1 of buprenorphine to naloxone and with the backinglayer formulated at pH of 4.25. This study was also designed todemonstrate the linearity of buprenorphine exposure across the range ofdoses. In addition, pharmacokinetic profiles following administration offour devices prepared according to formulation 5 (4×0.875/0.15 mgbuprenorphine/naloxone) was compared with those from a single deviceprepared according to formulation 6 that contained an equivalent dose ofactives (3.5/0.6 mg buprenorphine/naloxone).

This was an open label, single dose, 4-period crossover study in 20healthy subjects. Each subject received 4 doses of buprenorphine in thedevices of the invention in a random sequence, each dose separated by atleast 7 days. The doses administered were 0.875/0.15 mg, 3.5/0.6 mg,5.25/0.9 mg and 4×0.875/0.15 mg buprenorphine/naloxone in the devicesprepared according to Formulations 5, 6, 7 and 5, respectively.Naltrexone was co-administered approximately 12 hours and 30 minutesprior to and approximately 12 and 24 hours after the single study drugdoses. Serial blood samples for pharmacokinetic analyses were collectedpre-dose and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 210,240, 270, 300, 330 and 360 minutes post-dose and at 8, 10, 12, 24 and 48hours post-dose. Blood samples were analyzed using the establishedprocedures utilizing liquid chromatography and mass spectrometry(LC/MS). The selected pharmacokinetic parameters for buprenorphine andfree naloxone are shown in Tables 8 and 9.

TABLE 8 Selected Pharmacokinetic Parameters for Buprenorphine and FreeNaloxone for formulations 5 and 7 Formulation 5 Formulation 7 (0.875 mgbuprenorphine/ (5.25 mg buprenorphine/ 0.15 mg naloxone, 0.875 mgnaloxone, backing layer at backing layer at Pharmaco- pH 4.25) pH 4.25)kinetic Free Free Parameter Buprenorphine Naloxone BuprenorphineNaloxone Mean T_(max) (hr) 2.84 1.13 2.71 1.38 Mean C_(max) 1.15 0.04435.13 0.182 (ng/mL) Mean AUC_(last) 7.372 0.1166 33.28 0.4892 (hr *ng/mL) Mean AUC_(inf) 8.380 0.1202 36.19 0.5233 (hr * ng/mL) Absolute~60% — ~60% — Bioavailability

TABLE 9 Selected Pharmacokinetic Parameters for Buprenorphine and FreeNaloxone for formulation 6 and formulation 5 administered as 4 dosesFormulation 6 4 × Formulation 5 (3.5 mg buprenorphine/ (0.875 mgbuprenorphine/ 0.6 mg naloxone, 0.15 mg naloxone, backing layer atbacking layer at Pharmaco- pH 4.25) pH 4.25) kinetic Free Free ParameterBuprenorphine Naloxone Buprenorphine Naloxone Mean T_(max) (hr) 2.781.48 2.75 1.38 Mean C_(max) 4.03 0.179 3.89 0.182 (ng/mL) MeanAUC_(last) 24.77 0.4801 25.33 0.4892 (hr * ng/mL) Mean AUC_(inf) 27.320.4883 27.29 0.5233 (hr * ng/mL) Absolute ~60% — — — BioavailabilityThe results of the study indicate that changing the w/w ratio ofbuprenorphine to naloxone from 4:1 to 6:1 results in decreased naloxoneexposure that I s more in line with the exposure needed to precipitatewithdrawal if abused but not so much as to precipitate the withdrawal ifused as indicated. The results also indicate that C_(max) and AUC_(inf)of buprenorphine from formulations 5, 6 and 7 is dose proportional. Doseproportionality of buprenorphine C_(max) and AUC_(inf) are alsoillustrated by the graphs shown in FIGS. 2 and 3, respectively.

Example 5 Naloxone Withdrawal Study

The transmucosal devices of the invention that are prepared according toFormulations 1, 3 and 5 comprise relatively small doses of buprenorphineand naloxone (0.75 mg/0.19 mg and 0.875/0.15 mg buprenorphine/naloxone,as compared to 2 mg/0.5 mg buprenorphine/naloxone contained in theequivalent Suboxone® tablet). While the lower dose of the naloxone maybe beneficial for the patient using the product correctly, it may notproduce the expected aversive reaction experienced by those who aredependent on full-agonist opioids. Accordingly, the objective of thestudy was to determine the minimum effective dose of naloxone that willproduce a withdrawal response when administered with a 0.75 mg dose ofbuprenorphine in opioid dependent subjects. The secondary objective ofthe study was to determine whether administration of a 0.75 mg dose ofbuprenorphine without naloxone will produce a withdrawal response inopioid dependent subjects.

Study Population

The study was designed to include a total of 12 adult subjects thatcompleted the 4-period crossover. Subjects were eligible for inclusionin the study if all the following criteria applied:

subjects experienced chronic moderate to severe non-cancer pain that hasbeen treated >100 mg morphine equivalents per day for at least 3 monthsprior to the study;

subjects displayed signs and symptoms of withdrawal (i.e., COWS score≧5)following naloxone administration during the Naloxone Challenge.

Description of Study Medication

During the inpatient Treatment Visit subjects received a single, 3 mL IVbolus dose of each of the following treatments separated by at least 72hours:

a) Buprenorphine 0.75 mg (B)

b) Buprenorphine 0.75 mg+naloxone 0.1 mg (BN1)

c) Buprenorphine 0.75 mg+naloxone 0.2 mg (BN2)

d) Placebo (5% dextrose) (P)

Study Procedures

Eligible subject exhibited signs of withdrawal, e.g., had a positiveresponse (COWS≧5) to the Naloxone Withdrawal Test, followingadministration of up to eight 0.05 mg IV doses of naloxone.

Clinical Opiate Withdrawal Scale

The Clinical Opiate Withdrawal Scale (COWS) was used to evaluatesymptoms of opioid withdrawal. The scale contains 11 items to rate signsand symptoms of opioid withdrawal including pulse rate, gastrointestinalupset, sweating, tremor, restlessness, yawning, pupil size, anxiety orirritability, bone or joint aches, gooseflesh skin, runny nose, tearing.Each symptom is rated on a unique scale. Total scores for the scalerange from 0 to 48 with scores of 5-12 indicating mild withdrawal;scores of 13-24 indicating moderate withdrawal; scores of 25-36indicating moderately severe withdrawal; and scores>36 indicating severewithdrawal.

Opioid Agonist Scale

Subjects were asked to evaluate the following items: nodding, heavy orsluggish feeling, dry mouth, carefree, good mood, energetic, turning ofstomach, skin itchy, relaxed, coasting, soapbox, pleasant sick, drive,drunken, friendly, and nervous using a 5-point Likert scale (0=not atall, 1=a little, 2=moderately, 3=quite a bit, and 4=extremely).

Statistical Analysis

Descriptive statistics were used to summarize the results from the PDanalyses at each timepoint for each treatment group, without formalstatistical testing. A mixed effect model was fitted to the data for thechange from baseline in total score where the model included factorsfor: the overall mean change; fixed effects due to sequence; treatment,time and period; and a random effect for subject nested within sequence.The least squares mean changes and standard errors were obtained andused to construct 95% CI for differences between treatments in apair-wise fashion. Subject data collected after rescue time (i.e., timeat which the subjects reaches COWS total score of 13 or more) wereexcluded to minimize the confounding effect of rescue on the PDanalyses.

For COWS total score only, Time-to-Total score of ≧13 was calculated astime (hours) from first dose until the subject reports a total score of≧13. Subjects who did not reach a total score of 13 or more werecensored at 24 hours. This endpoint was summarized using theKaplan-Meier method and 95% CI presented for median for each treatmentarm.

Results COWS Total-Score, and Rescue Results

The number of subjects with COWS total score of at least 7 in the firsthour post dose is shown on the left side of FIG. 4. Eight subjects onbuprenorphine alone had a COWS value of at least 7 compared with 9 inthe buprenorphine plus naloxone 0.1 mg group, 12 subjects in thebuprenorphine plus naloxone 0.2 mg group, and two on placebo. Similarly,COWS≧13 were recorded for 6 buprenorphine subjects, 9 buprenorphine andnaloxone 0.1 mg subjects, 10 buprenorphine and naloxone 0.2 mg, and 2placebo patients. Two of the 15 subjects experienced withdrawal on eachof the study treatments, including placebo.

In the buprenorphine alone group, 7(47%) of the 15 subjects experiencedmoderate withdrawal with COWS score of at least 13, and all 7 wererescued. In the 8 subjects that did not receive rescue, the median COWSat 1 hour post dose was 1.

In the buprenorphine plus 0.1 mg of naloxone group, 9 subjects (60%) hadCOWS≧13 and all 9, plus an additional subject that was rescued. In the 5subjects that did not receive rescue, the median COWS at one hour postdose was 0.

In the buprenorphine plus 0.2 mg of naloxone group, 11 subjects (73%)had COWS scores of at least 13 and each of these received rescue. In the4 subjects that were not rescued, the median COWS at one hour post dosewas 3.

TABLE 10 Summary of COWS Total Scores and Rescue Results Parameter B (n= 15) BN1 (n = 15) BN2 (n = 15) P (n = 15) COWS >=13, n 7 (47%)  9 (60%)11 (73%) 2 (1%) (%) Rescued n (%) 7 (47%) 10 (67%) 11 (73%) 2 (1%)Median COWS 1 0 3 0 at One Hour Post Dose

Drug Effect Questionnaire (DEQ)—Observed Median Values 1 Hour Post Dose

Median DEQ responses at one hour in those subjects that were not rescuedare shown in Table 6 below.

The median DEQ scores for each parameter in all but the BN2 group werezero or nearly zero at one hour post dose. In contrast, the BN2 grouphad significantly higher scores on drug effect, nausea, bad effect,dizziness, and feeling sick.

The median score for good effect and how high are you was zero at onehour in all treatment groups.

TABLE 11 Median DEQ responces at one hour in subjects who were notrescued. Parameter B (n = 15) BN1 (n = 15) BN2 (n = 15) P (n = 15) Drugeffect 2 0 49 0 Nausea 0 0 38 0 Like drug 0 0 0 0 Good effect 0 0 0 0Bad Effect 0 0 27 0 Dizzy 0 0 14 0 Feel Sleepy 0 0 0 0 Feel sick 0 0 300 How high are 0 0 0 0 you

The results of this double-blind, placebo controlled study in opioiddependent subjects indicate that intravenous buprenorphine doses of 0.75mg have little abuse potential, and that the addition of naloxoneincreases both the incidence of withdrawal as well as negative drugevaluations. Thus, naloxone at doses of 0.1 and 0.2 mg, provide an abusedeterrent effect to a 0.75 mg dose of buprenorphine when administeredintravenously to opioid dependent subjects.

EQUIVALENTS

While the present invention has been described in conjunction withvarious embodiments and examples it is not intended that the presentteachings be limited to such embodiments or examples. On the contrary,the present invention encompasses various alternatives, modifications,and equivalents, as will be appreciated by those of skill in the art.

1. A mucoadhesive device for use in managing opioid dependence, thedevice comprising: a mucoadhesive layer comprising between about 0.075mg to about 12 mg of buprenorphine having a pH in a range between about4 to about 6; and a backing layer comprising between about 0.0125 mg toabout 2 mg of naloxone having a pH lower than said mucoadhesive layerand in a range of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 2. The mucoadhesive device of claim 1, wherein themucoadhesive layer and the backing layer comprise different combinationsof polymers.
 3. The mucoadhesive device of claim 1 wherein themucoadhesive layer is buffered to a pH of between about 4 to about 6 andthe a backing is buffered to a pH lower than said mucoadhesive layer andin a range of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 4. The mucoadhesive device for use in managingopioid dependence of claim 1, wherein the mucoadhesive layer comprisesbetween about 1 mg to about 1.5 mg of buprenorphine having a pH in arange between about 4 and about 6; and the backing layer comprisingbetween about 0.145 mg to about 0.2 mg of naloxone having a pH lowerthan said mucoadhesive layer and in a range of up to about half a pHunit below said pH range of said mucoadhesive layer.
 5. The mucoadhesivedevice for use in managing opioid dependence of claim 4, wherein themucoadhesive layer and the backing layer comprise different combinationsof polymers.
 6. The mucoadhesive device of claim 4, wherein themucoadhesive layer is buffered to a pH of between about 4 to about 6 andthe a backing is buffered to a pH lower than said mucoadhesive layer andin a range of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 7. The mucoadhesive device for use in managingopioid dependence of claim 1, wherein the mucoadhesive layer comprisesbetween about 2 mg to about 2.5 mg of buprenorphine having a pH in arange between about 4 and about 6; and the backing layer comprisingbetween about 0.3 mg to about 0.4 mg of naloxone having a pH lower thansaid mucoadhesive layer and in a range of up to about half a pH unitbelow said pH range of said mucoadhesive layer.
 8. The mucoadhesivedevice for use in managing opioid dependence of claim 7, wherein themucoadhesive layer and the backing layer comprise different combinationsof polymers.
 9. The mucoadhesive device of claim 7, wherein themucoadhesive layer is buffered to a pH of between about 4 to about 6 andthe a backing is buffered to a pH lower than said mucoadhesive layer andin a range of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 10. A mucoadhesive device for use in managing opioiddependence, the device comprising: a mucoadhesive layer comprisesbetween about 4 mg to about 4.5 mg of buprenorphine having a pH in arange between about 4 and about 6; and a backing layer comprisingbetween about 0.6 mg to about 0.7 mg of naloxone having a pH lower thansaid mucoadhesive layer and in a range of up to about half a pH unitbelow said pH range of said mucoadhesive layer.
 11. The mucoadhesivedevice of claim 10, wherein the mucoadhesive layer and the backing layercomprise different combinations of polymers.
 12. The mucoadhesive deviceof claim 10, wherein the mucoadhesive layer is buffered to a pH ofbetween about 4 to about 6 and the backing layer is buffered to a pHlower than said mucoadhesive layer and in a range of up to about half apH unit below said pH range of said mucoadhesive layer.
 13. Amucoadhesive device for use in managing opioid dependence, the devicecomprising: a mucoadhesive layer comprises between about 6 mg to about6.5 mg of buprenorphine having a pH in a range between about 4 and about6; and a backing layer comprising between about 1 mg to about 1.1 mg ofnaloxone having a pH lower than said mucoadhesive layer and in a rangeof up to about half a pH unit below said pH range of said mucoadhesivelayer.
 14. The mucoadhesive device of claim 13, wherein the mucoadhesivelayer and the backing layer comprise different combinations of polymers.15. The mucoadhesive device of claim 13, wherein the mucoadhesive layeris buffered to a pH of between about 4 to about 6 and the a backinglayer is buffered to a pH lower than said mucoadhesive layer and in arange of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 16. A method of managing opioid dependence byadministering to a subject in need thereof a device for directtransmucosal delivery of buprenorphine to a buccal surface, the devicecomprising: a mucoadhesive layer comprising between about 0.075 mg toabout 12 mg of buprenorphine having a pH in a range of between about 4and about 6; and a backing layer comprising between about 0.0125 mg toabout 2 mg of naloxone having a pH lower than said mucoadhesive layerand in a range of up to about half a pH unit below said pH range of saidmucoadhesive layer.
 17. The method of claim 16, wherein the mucoadhesivelayer and the backing layer of said device comprise differentcombinations of polymers.
 18. The mucoadhesive device of claim 16,wherein the mucoadhesive layer is buffered to a pH of between about 4 toabout 6 and the a backing is buffered to a pH lower than saidmucoadhesive layer and in a range of up to about half a pH unit belowsaid pH range of said mucoadhesive layer.
 19. The mucoadhesive device ofclaim 1, wherein the w/w ratio of buprenorphine to naloxone present inthe device is 6:1.